Features

Targeting drug safety in the ICU

An interview with Clinical Pharmacist Dr. Lisa Burry

By Natalie Osborne

In the intensive care unit (ICU), a multidisciplinary team of health care professionals must work in tandem to treat critically ill patients. This includes prescribing high-risk medications to severely ill patients while balancing efficacy, minimizing side effects and avoiding harmful drug interactions. Enter the Clinical Pharmacist; professionals trained in pharmacology and clinical medicine who make the rounds in the ICU everyday to ensure patients are receiving safe and efficacious drugs.

It was this bedside interaction that drew Dr. Lisa Burry to the PharmD program at the University of Toronto (UofT). She had already completed a BSc in pharmacy and worked for four years as a hospital pharmacist in a small community hospital when her mentors encouraged her to pursue advanced clinical care training. She was accepted into one of just six spots in the post-doc PharmD program and hired in the Critical Care Clinical Pharmacy Specialist position at Mount Sinai Hospital even before graduation. Now, years later, Dr. Burry has decided to go back to school for yet another doctorate—this time a PhD at the Institute of Medical Science.

As a Clinician-Scientist at Mount Sinai and Assistant Professor in the Leslie Dan Faculty of Pharmacy at UofT, Dr. Burry is already an accomplished researcher. She fully credits the clinical research-centric ICU she works in for involving her in as many projects as possible from the very start of her career, and eventually encouraging her to lead her own studies. Dr. Burry is particularly interested in sedation, delirium, and pain relief in critically ill patients. Due to their serious illness as well as invasive life-saving procedures, many ICU patients experience agitation, anxiety, sleep deprivation, and pain.

“My research has focussed on patient and drug safety, and symptom management. For example, if we’re giving a patient a drug to relieve their agitation, I want to determine; what’s the best option? How long do we need to give it? And how can we wean them off it once they leave the ICU?” Dr. Burry further explains, “As patients’ symptoms evolve over time, the treatment plan is also going to evolve. We need a clear plan for when some of these drugs are going to stop, because there are consequences to many of these drugs in terms of prolonged hospitalization and longterm addiction potential.”

Delirium, associated with medications or severe acute infections, is a common symptom in the ICU. Dr. Burry and colleagues wanted to understand which common ICU drugs increased the risk of delirium, so they followed 550 ICU patients, quantifying every psychoactive drug they received and assessing them for delirium daily. Then, they ran models to assess if any of the drugs were independently associated with delirium, accounting for other potentially confounding predictors such as age and sex (e.g., older men are more likely to have delirium).

They identified two classes of drugs— benzodiazepines and anti-cholinergic drugs—that were independently associated with delirium. They also determined the dose exposure of these drugs also increased delirium risk.

Lisa Burry, BSc Pharm, PharmD

Clinician Scientist & Clinical Pharmacy Specialist, Dept. of Pharmacy, Mount Sinai Hospital

“We know these drugs were potentially problematic, so now we need to understand what to give our patients instead,” Dr. Burry says. “Offering no treatment is not an option, because the agitation, delirium, and pain management issues are still going to be there, so we need to find better alternatives.”

While Dr. Burry’s previous research has focussed on clinical practices within the ICU, she is now following patient outcomes after hospital discharge. For her thesis, Dr. Burry is focussing on geriatric patients (people over 65 years) who make up a large proportion of those admitted to Canadian ICUs. She is using the Institute for Clinical Evaluative Sciences (ICES) database to determine if patients discharged from the hospital after an episode of critical care are being sent home with benzodiazepines and antipsychotic drugs (e.g., to help with symptoms like sleep disturbances and agitation). She will identify risk factors associated with becoming an “acute user” (filling a prescription within a week of discharge) versus a “chronic user” (multiple prescription refills over six months). Dr. Burry will also track the outcomes of patients who are sent home with these drugs, such as emergency department visits, and rehospitalization. “We know that some of these drugs are associated with falls in elderly people, but nobody has specifically looked at elderly patients who have survived an ICU stay—people we know had a major, severe illness and are more likely to be very frail,” explains Dr. Burry. “I’ll be looking at whether use of these drugs in this particular patient population is increasing the risk of falls, fractures, re-hospitalization, emergency visits and deaths.”

Her planned work will also help her identify which patients should be targeted to receive alternative treatments or weaning of newly initiated drugs; this could be either a different drug, or nonpharmacological strategies that offer comfort and care. One alternative treatment for delirium could be melatonin. Outside of her thesis work, Dr. Burry has recently completed a triple-blinded randomized controlled trial to assess the feasibility of using two different doses of melatonin versus placebo to prevent delirium in ICU patients. Since three quarters of delirium patients have sleep/wake abnormalities, melatonin may reduce delirium by improving patient’s sleep quality and reducing agitation at night (as well as exposure to drugs given to relieve agitation).

While returning to the classroom as a student after being out of school for a long time was a challenge, Dr. Burry believes that being a working adult with two degrees under her belt gave her a better understanding of what she needed. It also helped her target her learning a little better than she could have coming straight from her BSc in pharmacy. She encourages other health care practitioners with an interest in research to pursue advanced research training.

“I think an MSc or PhD is extremely valuable, even for someone who has as much research experience as I do. The formalized training helps solidify what you do know and identify gaps,” says Dr. Burry “This program has not only given me new knowledge, it’s also reinforced previous learnings and provided the underlying reasons for ‘why things should be done a certain way’ when it comes to certain research methodologies, and I was missing that.”

“I think the fluidity and flexibility of the IMS facilitates people like me to come back and do more training, compared to other more rigidly structured graduate programs that are more of a ‘one-way’ pipeline,” says Dr. Burry. “The IMS allows people from many different disciplines to get extra training and meets the needs of adult learners.”

By Mikaeel Valli

An average of ten Canadians die of suicide every day.1 Across the globe in high income countries, suicide is the second leading cause of death in youths aged 15 to 24 following accidental injury.2 In most western countries, youth suicide is often linked to mental illness, especially depression. More sobering still is that an upwards of 80% of youth do not have access to treatment to address their mental health needs when and where they need it.3

School boards have been doing their best to foster a healthy and supportive learning environment for children and youth. However, the school mental health support system is overloaded with long wait lists and with fewer psychologists providing direct service in public systems. Within the context of ever-increasing needs, it is not surprising that educational facilities can become “more reactive, rather than proactive as a result” explained Paula Conforti. She has been a licensed Member of the College of Psychologists of Ontario for the past 20 years and works with school boards to help assist children and youth with mental health challenges. In an effort to address these increasing needs, Conforti additionally sought Registration with the College of Regulated Psychotherapists to supervise those in the school system who are seeking this registration path. The IMS Magazine had the pleasure of interviewing Conforti about her perspective on this pressing topic.

“There is a need for more scalable and rigorous research that can prove the value of early interventions that will effectively decrease suicidal ideation and attempts among youth,” Conforti explained. Early intervention is key to improving the course of various mental health disorders. Additionally, population-evidence based interventions set the stage for stakeholders within the community to better support, proactively respond to, and understand underlying mental health challenges. Conforti expressed that she’s “always been very open to helping others to not only realize their potential and build on their successes, but to assist them in understanding how their core beliefs shape their decisions and reactions.” Given her passion and the gaps she observed in the school board system, she decided to go back to school to pursue her PhD with the University of Toronto’s Institute of Medical Science (IMS) graduate program. With her intention to do translatable research that directly benefits the needs of children and youth within the school boards, she had the pleasure of joining Dr. Mark Sinyor’s lab. Dr. Sinyor is a psychiatrist and associate scientist at Sunnybrook Health Science Centre.

Dr. Sinyor’s lab is focused on suicide prevention and mental health literacy in youth, which is aligned with Conforti’s goals. It is increasingly clear that youths need novel, innovative, and experiential ways to learn about mental distress and to develop a sense of resilience to overcome this distress. Together with Dr. Sinyor, Conforti and many other colleagues established a project that aims to increase mental health literacy and coping skills to grades seven and eight in schools within the GTA that elegantly fuses Cognitive Behavioural Therapy and the novel Harry Potter & the Prisoner of Azkaban.

“We chose middle schoolers because this is an age group where you start to see a rise in depression, anxiety and youth who die by suicide,” Conforti explained. “We are anticipating that our intervention will improve student wellbeing, decrease depression and anxiety ratings, and have an overall effect on decreasing suicidal ideations and attempts. The intervention is accomplishing this rather eloquently without ever directly mentioning suicide. Hence, if results show an improvement in student wellbeing, we are interested in seeing if these gains can be maintained at the high school level, ultimately resulting in an overall significant decrease in suicidality.”

Many do not know that J.K. Rowling—the author of the Harry Potter series---suffered from depression and was seeking treatment for it while writing the third novel—the Prisoner of Azkaban. Rowling channeled her experience with depression into the story by manifesting it as creatures called “Dementors” which serve as an allegory for

Paula Conforti

Graphics by Janell Lin

depression. “Dementors” are described as figures that suck out all the happiness from the victims, causing sadness, hopelessness and despair. The author also infused many coping strategies that she learned in her life that helped combat the Dementors in the story. “There are many comparisons used in the novel that lends itself to the mental health literacy concepts that we are trying to teach” said Conforti. This project is integrated into the English curriculum and taught by teachers who follow a protocolized manual that describes the main concepts that need to be imparted for each chapter. However, teachers are given latitude to customize and tailor the curriculum to the needs of their classroom.

Through this project, “students are given tools to recognize and normalize distress in themselves and others along with tips to facilitate help seeking. They can employ some of the strategies such as stress-busters or identifying errors in thinking and basic cognitive restructuring to help them,” Conforti explained. “The lessons afford students the opportunity to self-express in very safe ways, or if they are a little more reserved, they can perhaps creatively identify and share their thoughts through discussion of the characters in the novel” Conforti added enthusiastically. To quantitively assess the effectiveness of this mental health literacy program, self-report questionnaires have been distributed to roughly 525 students whose parents have consented to date, at various time points, to assess changes in emotional functioning. On a qualitative level, the research team will communicate with the students and teachers about their experience and feedback regarding the program through semi-structured interviews and focus groups. Viewing this literacy project from a school psychology perspective, Conforti expressed, “This is brilliant because it is teacher delivered within the classroom, lends itself to transcending language and culture, and normalizes the conversation about stressors affecting youth. I think this will have a profound effect as the kids will realize they are not alone with regards to how they are thinking and feeling.” The entire research team aspires to scale the intervention across the globe, which in turn has the potential to reduce the overall cost of mental health services, reduce suicide ideations and attempts, and improve youth resilience and positive coping.

When Conforti returned to school to do this research project with the IMS, we asked her what she has learned in her research that she would like to convey to practicing mental health professionals. “There are many professions and disciplines that are aware of the rise in mental health needs. However, I think we should all be afforded time to self-reflect so we can determine how we might collectively continue to make an impactful difference in meeting the needs of the many vulnerable groups who are in our schools and universities including aboriginals, LGBTQ2, multicultural, low socioeconomic status, and youth transitioning to young adults. With the prevalence rates that we are seeing, some as high as 25%, that’s potentially 250 students in a class of 1000 with mental health needs. With 200 students not accessing outside community support because of barriers to care and/or preference to be seen within the educational system, there is a need to find better and novel frameworks to intervene.” make it a priority to find creative ways to alleviate these barriers and encourage, support, and fund research to shed light on this. “Data speaks volumes. Research and data will prompt ministries and government agencies to realize responsible allocation of provincial mental health funds ear marked by the federal government should flow to school systems as well as health agencies,” she explained.

Going forward, Conforti envisions that schools and post-secondary institutions should create a school health hub embedded in the school system and research this framework to improve access to holistic services to those students in need. Ontario health and education systems often have what can be perceived as conflicting (and complimentary) mandates. It is counterintuitive to separate mental health and education because academic success depends on accessing “the whole student” which sets the stage for flourishing. However, the complex care medical environment is starting to recognize the need for integrated service. She also would like to see the “mandate for a credited mental health and wellness course that emphasizes the importance of self-care, goal setting, self-reflection, and mental and physical awareness.”

References

1. Public Health Agency of Canada. Government of Canada [Internet]. Canada.ca. Government of Canada; 2019 [cited 2020 Mar 15].

Available from: https://www.canada.ca/en/public-health/services/ suicide-prevention/suicide-canada.html 2. Patton GC, Coffey C, Sawyer SM, et al. Global patterns of mortality in young people: a systematic analysis of population health data.

The Lancet. 2009;374(9693):881–92. 3. Children and Youth [Internet]. Mental Health Commission of

Canada. [cited 2020 Mar 15]. Available from: https://www.mentalhealthcommission.ca/English/what-we-do/children-and-youth

MAKING WAVES IN AN AMBULANCE:

Ian Drennan on becoming a Paramedic Scientist

By Laura Best

Ian Drennan enjoys exploring the unknown; for him, a challenge is not a deterrent but an invitation. When he is not working to finish up his PhD at the Li Ka Shing Knowledge Institute or at the hockey rink with his kids, Ian is on the frontlines of healthcare as an advanced care paramedic. What quickly became clear in the short time we had to chat is that Ian thrives in novel environments. Being one of only a few paramedics in Canada pursuing a research-based doctoral degree, he has a unique perspective that influences the research questions he asks and the contextualization of his findings. He was eager to share his experiences and why he chose to pursue not only a professional degree, but also a graduate degree at the University of Toronto’s Institute of Medical Science (IMS) program.

Ian’s career path commenced at the University of Guelph, where he completed a Bachelor of Science in Kinesiology and first realized his passion for clinical care. Soon after, he transitioned to Humber College for his Primary Care Paramedic Diploma and enjoyed the fast-paced environment. “It has up days and down days, and you’re busy – it’s always different,” he shared. “Every scene you arrive at is different, every call leaves you learning something new.” Constantly walking into the unknown was stimulating and challenging—until it wasn’t anymore. After four years as a paramedic in Simcoe County and York Region, Ian began to feel comfortable in his role and “came to the realization that doing frontline work for the next 30 years wouldn’t be for him. [He] didn’t want to leave the profession, just wanted to do something new with it.” He felt as though “there was something more he could offer.” It was at this point that Ian began the search for a new perspective on paramedicine. After reviewing his potential options, Ian was intrigued by the way that research can inform guidelines and translate into clinical practice. He was inspired by paramedics in other provinces and countries who “forged ahead and created a better role where paramedics are really integrated in the medical system.” And, though it was uncommon for paramedics in Canada to pursue doctoral degrees at the time, Ian decided to enroll in graduate studies at U of T.

Under the supervision of Dr. Laurie Morrison, Ian’s doctoral work used an existing database at St. Michael’s Hospital in Toronto to develop different risk stratification tools and clinical prediction rules for post-cardiac arrest patients in the ICU. When patients arrive in hospital after a cardiac arrest, it is difficult to tell if they will recover, “a sort of grey period,” Ian explained, and current trials looking at different treatments for cardiac arrest patients or any prehospital treatments have often yielded negative findings. The idea was to use these tools clinically to find the probability of a good or poor outcome, and potentially learn when to focus a treatment option on one group of patients, in which there may be better efficacy.

Overall, Ian’s main focus was to develop a methodology that could be broadly applied to different areas of medicine. He expressed that he “has a whole list of things he wants to tackle after his PhD,” and hopes “to forge [his] own clinician scientist spot, as a paramedic scientist.” Having perspective from being on the frontline as a paramedic has only benefited the diverse thinking with which Ian has approached his research. It allows him to “think about what the next big research questions will be…and is helpful when putting some rational or implications behind your findings.” This unique dual experience has also allowed Ian to feel confident in bringing a valuable

“The paramedic role has been a unique twist to academia that most places are not as familiar with yet. The biggest challenge now is that I’m getting near the end – the now what”?”

Paramedic AMBULANCE

perspective to the panel discussions and committees he has sat on throughout his graduate degree.

At the time of our interview, Ian was just finishing up his degree*. When asked about it, he replied “It’s been a bit of a journey, I’ve had some hiccups along the way… There’s been lots of good opportunities too. The paramedic role has been a unique twist to academia that most places are not as familiar with yet. The biggest challenge now is that I’m getting near the end – the now what?” He went on to explain that “for paramedics, only a few with PhDs… not only is there no path, but for most people it’s not even on their radar. When you say, ‘I’m a paramedic with a PhD’, the reply is often ‘oh, I’ve never thought about that before’…I’m trying to forge my own clinician scientist spot, as a paramedic scientist and it’s challenging.” Despite his uncertainty, Ian will continue to break new ground in the near future, as he has secured a unique job at Sunnybrook hospital that will allow him to meld his expertise as a paramedic and a researcher. “Part of the role will be to oversee clinical trials…and the other part will be to do my own research,” he explained. His resilience in new environments was apparent as he modestly listed some of the options afforded by his dual career path, ultimately praising the flexibility of his new role and relying on his own ability to figure it out.

After twelve years of service as a paramedic and eight as a researcher, I asked Ian about any tidbits of wisdom that have impacted him along the way. After a mindful pause, he emphasized that “if you have time and energy, you can do it. Find a supervisor that can guide you through the process.” Some of the best advice that Ian received from his own supervisor was that “collaborating is by far the best thing you can do and being able to collaborate is the best skill you can learn.” When expanding on his own takeaways from his degree experience, Ian advised to “take time during your degree to learn skills, learn how to do research and move on with your career,” as your project will inevitably grow but try your best to “keep it manageable.”

Through the cumulation of knowledge gained in his unique set of experiences, Ian is well-positioned to make big waves in the paramedicine field here in Ontario. He hopes to leverage his clinical and research perspectives to improve emergency healthcare from multiple infusion points. And when asked what he does in his ample amount of time off, Ian chuckled and replied that he and his family try to stay active as much as possible. Even if that often looks like travelling between hockey arenas with the kids for their many team commitments, they always manage to find some time to for a pick-up game here and there.

* Since the time of the interview in March 2020, Ian has successfully defended and submitted his doctoral thesis.

Photo provided by Ian Drennan

Imaging Brains and Treating Hearts:

An Interview with Esmaeil Mansouri

By Mashal Ahmed

Apart-time registered nurse (RN) at St. Michael’s Hospital and a full-time Master’s student at IMS, Esmaeil Mansouri has struck a unique balance between his dual roles as a healthcare provider and clinical researcher. However, unlike many healthcare workers, for whom problems encountered on-the-job might pique interest into research, Mansouri’s journey began at the opposite end: with clinical inquiry.

After graduating from the University of Toronto in 2014 with a Bachelor of Science in Neuroscience and Chemistry, Mansouri began working at the Centre for Addiction and Mental Health (CAMH) as a research assistant. This position eventually led him into his current Master’s program, which he began in 2018. For the past six years Mansouri has worked with the Human Brain Imaging Lab under the supervision of Dr. Isabelle Boileau to better understand the biological mechanisms underlying mental illness and substance use disorders (SUDs).

SUDs impose a significant social and economic burden on society. Alcohol use disorder, for example, accounts for an average cost of $14.6 billion in Canada every year.1 Often, patients suffering from SUDs present with multiple comorbid psychiatric disorders, including bipolar disorder, major depression, antisocial personality disorder, general anxiety disorder, and dependence on other drugs,2 which further magnify mental, physical, and socioeconomic strains. Despite the prevalence of these disorders, treatments remain sub-optimal. This highlights the need to better understand the neurobiological under-pinning’s of such disorders.

Mansouri’s research has focused on using positron emission tomography (PET) and autoradiography imaging to learn more about the interaction between the brain’s cannabinoid and dopaminergic systems; both of which have been implicated in addiction and reward-related behaviours. PET is a nuclear imaging technique that uses a radioactive tracer to measure metabolic processes within the body. Mansouri’s project employs the radiotracer [C-11]-(+)-PHNO to measure in vivo dopamine D2/3 receptor binding.

“There is growing interest in the dopamine D3 receptor due to its pivotal role in addiction,” Mansouri explains. “Preclinical, post-mortem, and brain imaging studies have shown an upregulation of this receptor in stimulant users.3 Furthermore, a genetic variation (C385A) in an endocannabinoid system enzyme called “fatty acid amide hydrolase” (FAAH) has been associated with the same type of reward-related behaviours that are linked to dopamine D3 receptors.”

Mansouri’s imaging results demonstrate higher [C-11]-(+)-PHNO binding and D3 receptor expression in patients with the FAAH genetic variant (C385A).4 This genetic variation (C385A) results in lower FAAH activity, which has been associated with SUDs.5,6 “It’s exciting because we replicated this finding in mice as well. These results suggest that FAAH may serve as a novel therapeutic target for SUDs, which in turn, could spark interest in the employment of FAAHtargeted treatment options”, he explains. “Modulation of FAAH activity within the endocannabinoid system could have beneficial effects on the dopaminergic system, aiding in the treatment of SUDs.”

As the interview continues, we walk through the bright halls of the Research Imaging Centre at CAMH. Mansouri leads us into one of the patient prep rooms. “While preparing patients for imaging procedures I came to really enjoy the element of patient interaction; building rapport, learning uniquely different life stories, and providing emotional support when needed.” Mansouri explains. “Out of curiosity, I began talking to CAMH nurses to get a sense of their job experiences. It was these direct patient interactions and discussions that piqued my interest in clinical care and nursing. I loved my role in research, but I also wanted to make a difference on an individual basis.”

ESMAEIL MANSOURI, BSc, RN

MSc Student, Institute of Medical Science, University of Toronto

I learn about the brain...

... and help treat the heart.

A common misconception in research as well as the medical field in general, is that one’s area of expertise should be very specific and niche. While it is true that researchers and clinicians should be knowledgeable in their field, this notion should not hinder exploration of other areas, medical or otherwise. Branching into new endeavours promotes personal growth and provides broader perspective into one’s original field of work. That was the case for Mansouri.

Mansouri completed nursing school in 2017 and began working as an RN in the Cardiovascular Intensive Care Unit (CVICU) at Toronto General Hospital in January 2018. “It was a big leap to go from working in a mental health hospital to the CVICU. A number of people questioned the seemingly great difference between my research and clinical work.” Yet for Mansouri, this was an exciting transition. “From my perspective I was bringing the patient interaction skills I had developed from working with mentally vulnerable populations and applying them to a different set of patients”, he explained.

Patients admitted to the CVICU are either suffering from acute coronary syndromes, recovering from a major cardiothoracic-related surgery, or receiving critical treatment for a chronic cardiothoracic illness. Due to the severity of their ailments, these individuals often experience a roller-coaster of emotions, ranging from depression to extreme anxiety to delirium. “Having a background in mental health helps me better connect and understand these additional challenges. In turn, this allows patients to more easily build trust and have a more comfortable hospital experience. I like to tell people ‘I learn about the brain and help treat the heart’”.

Mansouri’s experience in research also helped him understand the importance of transitioning towards evidence-based clinical practice. A few decades ago, many medical procedures were anecdotal; if they worked for a handful of patients, surely they would work for others presenting with similar symptoms, right? Today, hospitals are moving away from this form of thinking and implementing practices that are based on reliable medical research and peer-reviewed literature. “My exposure to the scientific method taught me about the importance of evidence-based medicine early in my career, and I carry this knowledge forward through my job.”

“What about vice versa? What has your role as an RN taught you about research?” I ask. “The bigger picture”, he answers almost immediately. “As graduate students, we can easily be consumed with the nitty, gritty details of our work; striving to find statistical significance in our hard-earned data. But does statistical significance equate to clinical relevance? Not always.” Mansouri continued, “Working in healthcare has taught me to step back from my research and question how this will translate to bedside. This form of thinking has also helped me keep my manuscripts and thesis focused on the main purpose: How will these findings contribute to the medical community?”

As one might expect, the workload from navigating a Master’s project and concurrently working as an RN can be overwhelming. Initially Mansouri was working fulltime, but it became very stressful to balance with the academic expectations of his program. To maintain a healthy balance with his dual roles and responsibilities, Mansouri has started working part-time as an RN. “I try to work night shifts and weekends at St. Micheal’s and come into the lab to work on my thesis project. I also make time for taking power naps, working out, and hanging out with friends. I think these breaks between school and work are essential to maintaining this busy lifestyle. There is no way to survive without it”, he laughs.

As his Master’s comes to an end this summer, Mansouri contemplates the next steps in his career. “My options are wide open. I definitely want to remain in the healthcare field. I might pursue my PhD or further my studies to becoming a nurse practitioner. But as always, I am keeping my options open!” For anyone considering a similar, unconventional route in medical research and healthcare: stay open-minded about your opportunities; you might just end up imaging brains and treating hearts.

References

1. 1Rehm J, Baliunas D, Brochu S, et al. The costs of substance abuse in

Canada 2002 (Highlights). Canadian Centre on Substance Use and

Addiction. 2006. 2. Grant BF, Stinson FS, Dawson DA, et al. Prevalence and cooccurrence of substance use disorders and independent mood and anxiety disorders: results from the national epidemiologic survey on alcohol and related conditions. Archives of general psychiatry. 2004

Aug 1;61(8):807-16. 3. Payer D, Balasubramaniam G, Boileau I. What is the role of the D3 receptor in addiction? A mini review of PET studies with [11C](+)-PHNO. Progress in neuro-psychopharmacology and biological psychiatry. 2014 Jul 3;52:4-8. 4. Mansouri E, Nobrega JN, Hill MN, et al. D3 dopamine receptors and a missense mutation of fatty acid amide hydrolase linked in mouse and men: implication for addiction.

Neuropsychopharmacology. 2019 Nov 27:1-8. 5. Boileau I, Tyndale RF, Williams B, et al. The fatty acid amide hydrolase C385A variant affects brain binding of the positron emission tomography tracer [11C] CURB. Journal of cerebral blood flow & metabolism. 2015 Aug;35(8):1237-40. 6. Tyndale RF, Payne JI, Gerber AL, et al. The fatty acid amide hydrolase C385A (P129T) missense variant in cannabis users: studies of drug use and dependence in Caucasians. American journal of medical genetics part b: Neuropsychiatric genetics. 2007

Jul 5;144(5):660-6.